Interleukin (IL)-22, which is derived from innate lymphoid cells (ILC)-3 and Th17 cells, plays an important role in intestinal host defense since mice deficient in IL-22 or its receptor, IL-22Ra1, are highly susceptible to multiple models of intestinal inflammation. In the past 10 years substantial progress has been made in our understanding of the IL-22-mediated mucosal host defense responses in the intestine; however, serious gaps in our knowledge remain. The pleiotropic effects of IL-22, coupled with the diverse array of intestinal cell types that express IL- 22Ra1, limit our ability to target this pathway therapeutically. It remains unclear how IL-22 interacts with functionally distinct epithelial cell lineages (absorptive or secretory) and intestinal stem cells (ISCs). The goal of this proposal is to understand whether IL-22Ra1 signaling in Paneth and/or intestinal stem cell (ISCs) regulates IL-22-mediated protection. We will assess the mechanistic nature of that protection on distinct epithelial compartments using cell-specific knockout mice and recombinant IL-22.Fc protein approaches. Towards this end, we generated 1) entire gut epithelium, 2) Lgr5+ ISCs, and 3) Paneth cell-specific conditional IL-22Ra1 knockout mice. We have accumulated critical data that lack of intestinal IL-22Ra1 signaling leads to a defect in Paneth cell-specific functions as well as enhanced susceptibility to Salmonella Typhimurium. Thus, based on the strength of our preliminary results, we hypothesize that IL-22Ra1 signaling in Paneth cells modulates intestinal host defense by regulating post-translational modifications of a-defensins and maintaining ISCs niche. In specific Aim 1, we will determine whether IL-22Ra1 signaling in Paneth cells regulates post-translational modification of a-defensins and maintains ISCs niche. In Aim 2, we will investigate whether Paneth, ISCs and/or absorptive enterocytes-specific role of IL-22Ra1 signaling is required to control S. Typhimurium-induced inflammation. These studies will provide critical new mechanistic information about specific cellular niches of IL- 22Ra1-signaling in the gut and their involvement in disease development, maintenance and therapeutic outcomes.